JPS6330462A - Novel guanidinomethylbenzamide derivative and antiulcer agent containing said derivative as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (X is organic or inorganic acid residue). EXAMPLE:N-Phenyl-4-guanidinomethylbenzamide hydrochloride monohydrate. USE:An antiulcer agent. PREPARATION:A 4-guantidinomethylbenzoic acid expressed by formula II and aniline expressed by formula III are subjected to condensation reaction through dehydration in the presence of dicyclohexylcarbodiimide (hereinafter abbreviated to DCC) in a solvent and, as necessary, the resultant free product is converted into a salt, etc., to afford the aimed compound expressed by formula I. The reaction is carried out by using the compound expressed by formula III in an amount of 1.0-1.5 mol based on 1.0 mol compound expressed by formula I and DCC in an amount of 1.0-1.5 mol based on 1.0 mol compound expressed by formula II. Preferred reaction solvents are anhydrous acetone, THF, dioxane, pyridine, etc.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention relates to a guanidinomethylbenzamide derivative represented by the general formula (I) (wherein X represents an organic or non-acidic acid residue), and a guanidinomethylbenzamide derivative represented by the above formula This invention relates to an anti-ulcer agent containing the compound of (I) as an active ingredient.

[Prior Art] Many compounds have been proposed for the treatment and prevention of gastrointestinal ulcers. For example, JP-A-57-197256 states that to(phenyl)-trans-4-guanidinomethylcyclohexanecarboxamide hydrochloride (hereinafter referred to as a control compound) represented by the following formula has an antiulcer effect. However, the anti-ulcer effect was not sufficient and the toxicity was relatively strong.

[Means for Solving the Problems] The present inventors synthesized various compounds and investigated their anti-ulcer effects. As is clear from the results, it was found that this compound has excellent anti-ulcer activity and extremely low toxicity, which could not be expected from the control compound.

The compound of the present invention is represented by the above formula (1). The formula (I
> Examples of acid residues include FA-free acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as organic acids such as acetic acid, propionic acid, citric acid, lactic acid, tartaric acid, and para-toluenesulfonic acid. a-acids, among which pharmaceutically acceptable acid addition salts are preferred.

According to the present invention, the guanidinomethylbenzamide derivative represented by the compound (I> is prepared by combining, for example, 4-guanidinomethylbenzia<■> and aniline (U) in the presence of dicyclohexylcarbodiimide (hereinafter referred to as DCC). A dehydration condensation reaction is carried out in a solvent, and if necessary, the free product 1* is converted into a salt, and then compound (1) is produced from water or an aqueous medium under conditions that do not eliminate its water of crystallization. Compound (1) can be produced by drying to remove the attached water.

(I[) (III) Compound (n
) The amount of compound (1) used per 1.0 mol is i, o ~
The amount of DCC used is 1.0 to 1.5 moles. Preferred reaction solvents include acetone, tetrahydrofuran, dioxane, and pyridine, all of which are anhydrous. The reaction is completed by stirring at subtemperature for 10 to 80 hours or boiling and refluxing for 1 to 5 hours.

In addition, in the above reaction, compound (II>) or compound (
The acid addition salt of compound (1) can be directly obtained by reacting I[I] in the form of an acid addition salt under non-basic conditions.

On the other hand, when compound (n) and compound (1) are reacted in the form of a free base, compound (I) is obtained as a free base, which can be converted into an acidified Caro salt according to a conventional method. Further, the acid addition salt of compound (1) can be converted into other acid addition salts by a conventional salt exchange method. Thus, the compound (I) of the present invention can be administered orally or parenterally (for example, intramuscularly, subcutaneously, locally, etc.) as an antiulcer agent for the treatment and treatment of humans and other warm-blooded animals. Can be done.

When used as a drug, the compounds of the invention can be formulated into various forms suitable for oral or parenteral administration. For example, the compounds of the invention can be formulated with non-toxic pharmaceutically acceptable carrier materials commonly used for drugs of this type. Depending on the intended use, such drugs may be in solid form (e.g. tablets, capsules, granules, powders, granules, dragees, lozenges, etc.), semi-solid forms (e.g. ointments, creams, suppositories) and liquid forms. It can also be prepared in any form (injection, emulsion, suspension, lotion, tincture, spray, syrup, etc.). Thus, non-toxic pharmaceutically acceptable carrier materials that can be used include, for example, starch, gelatin, glucose,
Lactose, fructose, maltose, magnesium carbonate, talc,
Magnesium stearate, methylcellulose, carboxymethylcellulose (CMC) or its salts, gum arabic, polyalkylene glycol, distilled water for injection, rho
-Hydroxybenzoic acid alkyl ester, syrup, ethanol, propylene glycol, glycerin, petrolatum 1
Examples include non, force-bowax, and the like.

The agent may also contain other therapeutically useful agents, dispersants, antioxidants, preservatives, stabilizers, flavoring agents, binders, lubricants,
Salts, buffers, etc. can be included to alter the osmotic pressure.

The content m of the compound of the invention in the drug varies depending on its dosage form, but is generally in a concentration of 5 to 100% by weight for solid and semisolid forms, and 0.1% for liquid forms. It is desirable to contain the active compound in a concentration of ~10% by weight.

The dosage of the compound of the present invention can vary widely depending on the type of warm-blooded animal including humans, the severity of the symptoms, the doctor's diagnosis, etc., but in general, the dosage is 0.00% per day.
1 to 30 m3/; J, preferably 0.1 to 20 mg/N
It can be y. However, as mentioned above, depending on the severity of the patient's symptoms and the doctor's diagnosis, it is of course possible to administer an amount smaller than the lower limit or larger than the upper limit of the above range.

The above administration can be administered once a day or in divided doses.

[Effects of the Invention] The fact that the guanidinomethylbenzamide derivative represented by compound (I) of the present invention has an excellent antiulcer effect is as follows.
This can be proven by the following animal experiments.

The compounds used in the following animal experiments are indicated by the following symbols.

Surrounded Kinso A...Tophenyl-4-guanidinomethylbenzamide hydrochloride monohydrate (compound of Example 1) B...N-(phenyl)-trans-4-guanidinomethylcyclohexanecarboxamide hydrochloride (Control compound) Test 1 [Anti-stress ulcer effect] 1. Test method Takagi et al.'s method [Japanese Journal of...] 7
-Ma:Dology (Jap, J, Pharmacol,)
, Vol. 18, p. 9 (1968)]. After fasting for 24 hours, a test compound suspended in a 1% CMC aqueous solution was orally administered to SD male and female rats (8 weeks old, 6 to 8 animals per group) weighing 180 to 200 g, and then the rats were incubated for 15 minutes. The mice were placed in a stress cage and immersed in a bath of water at 24° C. to the depth of the xiphoid process of the sternum. After 18 hours of immersion in water, the rats were sacrificed with ether and their stomachs were removed, into which 12 ml of a 1% formalin aqueous solution was injected, followed by immersion in the 1% formalin aqueous solution for 15 minutes.

Next, the stomach was incised along the human surface, and the long axis (#) of each ulcer that had occurred on the gastric mucosa was measured under a dissecting microscope, and the sum (m) of the long axis of each ulcer was taken as the ulcer coefficient. Calculate the ulcer inhibition rate using the following formula and calculate the EDsol from the dose-ulcer inhibition rate curve.
I found a.

Ulcer suppression rate (%) = (1-苧) Xl 00 (in the formula, l
= ulcer coefficient of the drug-free group, m = ulcer coefficient of the test compound administered group. ) 2. Test results are shown in Table 1 below.

Test 2 Anti-ethanol ulcer effect] 1. Test method Robert's method [Gastroenterology, Vol. 77, 4
33 (1979)].

That is, SD male and female rats (8 weeks old, 6 to 8 rats per group) weighing 180 to 200'j were fasted for 24 hours and then treated with 1% C.
The test compound suspended in MC aqueous solution was orally administered, and 30 minutes later, ethanol (99.5%>ld) was orally administered. After 1 hour, the rats were killed with ether, the stomach was removed, and 1% formalin was added to it. After injecting 12d of aqueous solution, 1
% formalin aqueous solution for 15 minutes.

Thereafter, the ulcer index and ulcer inhibition rate were calculated in the same manner as in Test 1, and the EDs were calculated from the dose-ulcer inhibition rate curve.

11 rod 1; 51-〒i music toichi)) t--2, test results It is also shown in Table 1 below.

Test 3 Anti-indomethacin ulcer effect 1 1. Test method Method of Ryobe et al. [Japanese Journal of...] 7
- Macology (Jap, J, Pharmacol,),
Volume 29.

670, (1979)]. That is, 8-week-old SD male and female rats weighing 180-2009;
After fasting for 24 hours (6 to 8 animals per group), the test compound suspended in 1% CMC aqueous solution was orally administered, and then 15 minutes later,
Indomethacin (30 mg/Kg) dissolved in 3% aqueous sodium bicarbonate solution was administered subcutaneously. After 5 hours, the rats were killed with ether and their stomachs were removed and treated with 0.1% Pontamine Sky Blue (ponta!1Nne 5).
1% formalin aqueous solution containing 12
After injecting m1, it was immersed in a 1% formalin aqueous solution for 15 minutes. After that, in the same way as in Test 1, the ulcer coefficient,
Calculate the ulcer inhibition rate, and calculate the dose-ulcer inhibition rate curve, 'flA
I wanted an EDso field.

2. Test results It is also shown in Table 1 below.

Test 4 [Acute toxicity test/minimum lethal dose ()ILD)] 1,
Test method A test compound suspended in a 1% CMC aqueous solution was orally administered to 20-229 ddY male mice (4 weeks old, 5 mice per group) that had been fasted overnight, and the presence or absence of death of the mice was observed for 7 days. The lethal dose ()tLD) was determined.

2. Test results Shown in Table 1.

From the results shown in Table 1, Compound A of the present invention is more effective than Control Compound B in all of the anti-stress ulcer, anti-ethanol, and indomethacin-ulcer activities, and is moreover, when administered orally to mice. acute toxicity (
The minimum lethal dose) is 3 or more per 3,000 m3, which clearly indicates that the toxicity is extremely low.

Next, a humidification test was conducted to check the stability of Test Compound A.

Entabidankokihuangkirito1, test method test compound A100IrI! I was placed in a vial, humidified at 40'C and 75% RH, and changes in water content over time were measured. Note that the water content was determined by thermogravimetric analysis.

2. Test results Shown in Table 2.

As shown in Table 2, test compound A is a stable crystal whose weight does not change with humidity, and is suitable for solid preparations such as tablets, capsules, and fine granules.

The present invention will be further explained below with reference to Examples.

[Example] Example 1 (a) Production method of 4-guanidinomethylbenzoic acid hydrochloride 2N
17.7 g of S-methylisothiourea sulfate was added to 100 InIl of sodium hydroxide under cooling, and then 2N sodium hydroxide was added until the pH reached 11. A solution of 10 g of p-aminomethylbenzoic acid dissolved in 50 ml of boiling water was added to this liquid. This mixture was left at room temperature overnight and then cooled.
The precipitated crystals were collected by filtration, washed with cold water until neutral, and dried under reduced pressure. 99 d of 1N hydrochloric acid was added to the obtained crystals and heated to remove the formed insoluble matter. The filtrate was distilled off under reduced pressure and recrystallized from water-methanol (1:1) to obtain 8.4 g of 4-guanidinomethylbenzoic acid hydrochloride as white crystals.

l1ip: 227-230°C Inp <cm-'): 3400-3000.1
680 elemental analysis value (as C9H11N30z ・HCI): Calculated value (%) C, 47, 07: H, s, 27
:N, 18.30 actual value (%) C, 46,98:H
,s, 15 :N, 18.37(b) Process for producing N-phenyl-4-guanidinomethylbenzamide hydrochloride 1-eternal 4-guanidinomethylbenzoic acid hydrochloride obtained in (a) above 2.09 and Aniline 0.93 to pyridine 100
After adding and dissolving the mixture in a mixture of rr11 and dimethylformamide 40-, 1.0 g of DOG was added and reacted at room temperature for 70 hours. After the reaction was completed, 100% of water was added and stirred for 30 minutes, and then insoluble matter was filtered off. The filtrate was concentrated to dryness, the residue was washed with benzene ioom 1 and ethyl acetate 100 rd, and then re-crystallized twice from water to give 1.19 N-phenyl-4-guanidinomethylbenzamide hydrochloride monohydrate as white crystals. obtained as.

As a result of thermogravimetric analysis, this compound exhibited a weight change (-5%) corresponding to one molecule of water at 143°C.

Inp,; 183-184°C InpK''(crn-'> 3400-3000.
1680.1600ax MS (m/e); 268 (M”) Elemental analysis value (as C1sHqsNa 0-HCl・HzO)

Claims (1)

[Claims] 1. A guanidinomethylbenzamide derivative represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein X represents an organic or inorganic acid residue). 2.An anti-ulcer agent whose active ingredient is a guanidinomethylbenzamide derivative represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein X represents an organic or inorganic acid residue).